German Edition: DOI: 10.1002/ange.201601989Fluorine Chemistry Hot PaperInternational Edition: DOI: 10.1002/anie.201601989

Positioning a Carbon–Fluorine Bond over the p Cloud of an AromaticRing: A Different Type of Arene ActivationMaxwell Gargiulo Holl, Mark D. Struble, Prakhar Singal, Maxime A. Siegler, andThomas Lectka*

Abstract: It is known that the fluoro group has only a smalleffect on the rates of electrophilic aromatic substitutions.Imagine instead a carbon–fluorine (C¢F) bond positionedtightly over the p cloud of an aryl ring—such an orthogonal,noncovalent arrangement could instead stabilize a positivelycharged arene intermediate or transition state, giving rise tonovel electrophilic aromatic substitution chemistry. Herein, wereport the synthesis and study of molecule 1, containing a rigidC¢F···Ar interaction that plays a prominent role in both itsreaction chemistry and spectroscopy. For example, we estab-lished that the C¢F···Ar interaction can bring about a > 1500fold increase in the relative rate of an aromatic nitrationreaction, affording functionalization on the activated ringexclusively. Overall, these results establish fluoro as a through-space directing/activating group that complements the tradi-tional role of fluorine as a slightly deactivating aryl substituentin nitrations.

The fluoro group generally exhibits only a small effect on therates of electrophilic aromatic substitutions.[1] Reactionsinvolving putative s-complexes are usually slightly activatedby fluorine, whereas aromatic nitrations[2] that involveanalogous p-complexes[3] show deactivation. While suchclassical substituent effects have been well documented inaryl fluorides, we wish to approach the interaction froma different perspective; imagine instead a C¢F bond posi-tioned tightly and rigidly over the p cloud of an aromatic ring.Is it possible that such an arrangement could stabilizea positively charged nitroarenium ion intermediate[4] ortransition state, thereby giving rise to new reaction chemistryin which the fluoro group is now highly activating? Given theever increasing importance of fluorine to arene chemistry inparticular and organic chemistry in general, a fundamentallydifferent method of activating electrophilic substitutions is ofgreat interest.[5] For our part, we have recently reportedstudies on the generation of symmetrical fluoronium ions insolution,[6] suggesting to us that under the right conditionsfluorine could also play the role of an anchimeric assistor inreaction chemistry.

In this spirit, we report the synthesis of a molecule inwhich a C¢F bond is projected over the p-system of anaromatic ring, imbuing it with unique reactivity. Spectroscopy,crystallography, and reactivity tell the story of a species inwhich the C¢F···Ar interaction plays a prominent role inestablishing fluorine as a through-space directing/activatinggroup in aromatic substitutions that complements its tradi-tional role as an aryl substituent (Figure 1). As perhaps the

signature aromatic substitution reaction, we chose nitration asa candidate for initial studies.[7] The generally acceptedmechanism for classical nitrations involves the reaction ofa nitronium ion with an aromatic ring.[8,9] After p-complex-ation, this step forms a positively charged arenium ion, or“Wheland intermediate,” that we believed could be stabilizedwith the assistance of fluorine from above the p cloud of thering.[10]

In order to test our hypothesis, we sought to constructa system in which the fluorine atom is projected well withinthe hexagonal prism of space defined by the aromatic ring.Thus we imagined that the Diels–Alder reaction of dienophile2[11] with anthracene[12] would provide a product in which a C¢F bond is pointed directly towards one of the two aryl groups(Scheme 1). Heating a mixture of 2 and anthracene producedthe desired product 1 (1,2-dichlorobenzene, 180 88C, sealedtube, 72% yield).

The 19F NMR spectrum (300 MHz) of adduct 1 showeda single resonance at ¢180.5 ppm, split into a complexmultiplet. This resonance is within the range seen for othersecondary C¢F bonds,[13] an observation that, in isolation,made it initially unclear whether any notable interaction was

Figure 1. Inductive deactivation of fluoroarene versus fluorine’sthrough-space stabilization of arenium ion.

[*] M. G. Holl, M. D. Struble, P. Singal, Dr. M. A. Siegler, Prof. T. LectkaDepartment of Chemistry, Johns Hopkins University3400 North Charles Street, BaltimoreMD 21218 (USA)E-mail: lectka@jhu.eduHomepage: http://lectka.chemistry.jhu.edu/

Supporting information and the ORCID identification number(s) forthe author(s) of this article can be found under http://dx.doi.org/10.1002/anie.201601989.

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occurring. In fact, relatively little is known about through-space interactions of C¢F bonds with the interiors of aromaticrings—from the exterior, ring currents are believed to haveonly a minimal relative impact on the chemical shifts of thefluorine atoms of aryl fluorides.[14]

We hypothesized that the interior placement of fluorinewould result in an upfield shift in the 19F NMR spectrum, inanalogy to the well documented upfield shift[15] of hydrogen inC¢H bonds projected within the shielding zones of aromaticrings (indeed, analogs of 1 with inward pointing hydrogenatoms do see shielding, vide infra). In one impressiveprecedent, Pascal et al. have observed a large upfield shift(¢155 ppm) of the 19F resonance in a Si¢F bond projectedtowards the center of an aromatic ring in a cyclophane,attributed to a ring current effect.[16] In a recent example,Chang et al. instead observed downfield shifts in C¢F bonds,attributable in part to steric compression.[17] However, notethat the C¢F bonds in the latter case reside outside the prismand perhaps outside the shielding zone of the ring. Thus, thequestion of what happens when a C¢F bond is projectedwithin remains unsettled. In order to characterize 1, we thenturned our attention to control species, the first being alkene 3(Figure 2), in which a C=C double bond is positioned near theC¢F bond rather than an aromatic ring.[11] When the 19Fspectra of these two molecules were compared, we observedthe signal of 3 30 ppm downfield of 1, an observation that isroughly consistent with an enhanced ring current effect in thearomatic system.

On the other hand, when the 19F spectrum of in-fluoride1 was compared to that of out-fluoride 4 (the synthesis of 4 isshown in the Supporting Information), whose fluorine atom isconsiderably farther away from the aromatic ring, a differentobservation was made. The in-fluoride 1 resonates 15.8 ppmdownfield from out-fluoride 4, contrary to what we expected.To shed light on what is going on, we turned our attention todensity functional (DFT) calculations. Using the F–Ardistances and angles in the optimized structures of 1 and 4as starting points (wB97xd/6-311 + G** = “B97”),[18] weapproximated the interactions as virtual atoms positionedabove a benzene ring.[19] Employing the nucleus independent

chemical shift (NICS) protocol in Gaussian, we calculatedthat the virtual atom corresponding to the in-fluorine shouldbe more shielded than the “out” virtual atom (although thelatter is still within the shielding zone of the p cloud of thearene ring).[20] Something is therefore happening to deshieldthe 19F atom of 1. One explanation, consistent with ChangÏsresults, also involves steric compression. For example, 1 is lessstable than 4 by 8.3 kcalmol¢1 (at B97, see the SupportingInformation), mainly due to nonbonded interactions betweenF and the arene ring.[21] Congruently, Martin et al. have shownthat C¢H bonds that are aligned along the vertical C2 axis ofa C2v symmetric C=C bond (e.g. in ethylene) are deshieldedwhen present within 3.0 è of the horizontal plane of themolecule (even though NICS indicates this area to bea shielding zone).[22] Orbital compression[23] may be respon-sible for the deshielding—in our case, the electron cloudabout the fluorine atom would be distorted anisotropically.How can steric compression of the C¢F bond be otherwisequantified? One way is to examine 13C–19F NMR couplings—as the bond is compressed, the magnitude of the couplingincreases.[24,25] This is in fact what we find; the C¢F coupling isgreater in in-fluoride 1 than out-fluoride 4 by 21 Hz.

A crystal of 1 suitable for X-ray determination was grownfrom a mixture of CH2Cl2 and Et2O. The structure reveals thefluorine positioned slightly asymmetrically, but still well overthe aromatic ring (Figure 3). Intermolecular interactions inthe crystal lattice likely skew the position of the F atom andbreak the Cs symmetry of the molecule, as the nearest carbonatoms on the aromatic ring are ca. 2.68 and 2.75 è (2.72 è atB97) away. The molecule retains full Cs symmetry in silico;the predicted C¢F distance (B97) is 1.37 è, which isshortened a bit from the distance predicted for the out-fluoride 4 (1.39 è). This is consistent with the increased C¢Fcoupling in the NMR spectrum of 1 relative to 4.

In this study, X-ray data were collected at subatomicresolution (0.40 è) to obtain a more accurate description ofthe atomic electron density in the crystal. The experimentallyobserved density along the C¢F bond shows a slight aniso-tropy in which the electron cloud around the fluorine atomhas been distorted (Figure 4). A region of low density liesacross the bond, and is bent away from the C¢F line,consistent with bond compression. As a control, we were ableto draw a static deformation electron density map of a similarstructure that lacks the influence of the ring (see theSupporting Information). The C¢F bond in the control does

Scheme 1. Synthesis of 1.

Figure 2. Alkene 3 and arene 4.Figure 3. Displacement ellipsoid plot (50% probability level) of 1 at110(2) K.

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not deviate from the C¢F line. A noncovalent interaction(NCI) analysis (Figure 4) was also performed on 1 using themolecular coordinates of the crystal structure.[26] The modelpredicts a slightly attractive interaction between fluorine andthe arene, suggesting that a complex interplay of forces maybe at work.

The unique structure of 1 serves a dual purpose inmeasuring reactivity in electrophilic aromatic substitution.The aromatic ring proximate to fluorine (ring A) serves as theprobe, whereas unperturbed ring B (distal from F) serves asan internal control. A good place to start would be a commonsubstitution reaction such as a nitration. For example, theaddition of a nitronium ion to the position of ring A as in 5should generate partial positive charge at the arene carbonattached to the bridgehead. In turn, lone pairs on fluorine canexert a through-space stabilizing influence on the transitionstate, and the resulting arenium ion 5 as well.

Calculation of the corresponding Wheland intermediates5–10 (at various levels of theory that address long rangeinteractions and dispersion)[27] demonstrates this trend(Table 1). The in-F atom stabilizes, in a through-spacemanner, the A-ring derived intermediate 5 when comparedto the analogous B-ring intermediate 8, whereas in opposi-tion, the B-ring areniums 9 and 10 are favored over A-ringareniums 6 and 7. The geometry of 5 shows fluorine movingcloser to the ring towards carbon 4 (para to the nitro group ofring A) and enhancing the C¢FbbAr interaction in theprocess (2.53 è v. 2.72 è in 1, B97). The in-pointing hydrogengeminal to the nitro group does not interact with fluorine toany extent, leaving the C¢FbbAr interaction as the primarymeans of stabilization. In contrast, the seminal works of Cramand Hopf have shown that aromatic rings and certainsubstituents can act as H-bond acceptors in directing theelectrophilic substitution of paracyclophanes.[28] An atoms-in-molecules (AIM) analysis[29] of ion 5 shows a bond criticalpoint between fluorine and carbon 4 (1 = 0.020). The fluorineatom can also be described as acting as a Lewis base mediatedby the aromatic ring; it is unusual to see an organic fluorineatom acting in such a manner.

When 1 was treated with 1 equiv of ammonium nitrate ina 2:3 mixture of TFAA and MeCN at 25 88C,[30] diastereomer11 was observed exclusively and in high yield (89 %,Scheme 2). Control 4, designed to gauge the stereoelectronic

effect of the fluoro group, instead afforded a � 1:1 mixture ofA:B ring isomers (13). Being distant from the reactive centers,the out-F is shown to exert little directing effect on thenitration reactions. Note that the exact nature of the activenitrating species (and thus the p-complex) under theseconditions is not known and is beyond the scope of thiswork (it is posited to involve either a nitronium ion ortrifluoroacetyl nitrate).[31, 32] Thus for our computations, weemployed the Wheland intermediates as models rather thancalculated transition states or p-complexes.

Another control involves 12 (see the Supporting Infor-mation for the synthesis),[6b,33] in which the fluorine atom isreplaced by hydrogen. It is well established that hydrogenatoms can stabilize positive charge through m-hydrido bridg-ing[34] and would serve as a benchmark comparison of the roleof fluorine. Once again, a mixture of nitrated productsinvolving both rings A and B was observed (14).

Finally, a competitive rate study of the nitration reactionswas performed. Fluoride 1 was shown to react much morerapidly than either control 4 or 12, with a factor of 1500 beinga lower bound on this increase over 4 (measurement onlylimited by the S/N ratio of the NMR experiment, Figure 5),

Figure 4. Left: Static deformation electron density map in the planeH1, C1, F1 of 1, 2D slice along the molecule’s plane of symmetry.Violet regions represent electron density (positive) and green regionsrepresent holes (negative). Right: Noncovalent interaction (NCI) plotof 1. The bluish region between F and the arene indicates an attractriveinteraction (red regions are repulsive interactions).

Table 1: Computed relative energies of 10–15 [DErel ADB of arenium ions(Wheland intermediates)]. Functionals with dispersion and long rangecorrections were chosen).[18b, 27]

Method/Basis Set DErel [kcal]8–5 9–6 10–7

wB97xd/6-311+ G** 5.2 ¢2.5 ¢2.2CAM-B3LYP/cc-pvdz 5.5 ¢1.8 ¢2.2APFD/6-311 +G** 4.5 ¢1.9 ¢1.8LC-wPBE/6-311+ G** 5.9 ¢2.5 ¢2.2

Scheme 2. Starkly different reactivity of 1 compared to 4 and 12.

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presenting the most definitive and compelling evidence offluorine activation.

In conclusion, we have provided spectroscopic andcrystallographic evidence for a molecule in which a C¢Fbond is projected over the p-system of an aromatic ring. TheC¢FbbAr interaction plays a prominent role in reactionchemistry (e.g. an aromatic nitration), establishing fluorine asa significant through-space activating and directing group thatcomplements and contrasts its traditional role as a weaklyperturbing aryl substituent in electrophilic aromatic substitu-tions.

Experimental SectionGeneral experimental procedures and characterization data can befound in the Supporting Information. CCDC 1453396, 1453397,1455412, and 1455413 contain the supplementary crystallographicdata for this paper. These data can be obtained free of charge fromThe Cambridge Crystallographic Data Centre.

Acknowledgements

T.L. thanks the NSF (grant number CHE 1465131) forsupport. M.D.S. thanks JHU for a Rudolph SonnebornFellowship.

Keywords: arenes · aromatic substitution · carbocations ·fluorine · neighboring-group effect

How to cite: Angew. Chem. Int. Ed. 2016, 55, 8266–8269Angew. Chem. 2016, 128, 8406–8409

[1] a) J. F. Bunnett, R. E. Zahlerz, Chem. Rev. 1951, 49, 273 – 412;b) J. Rosenthal, D. I. Schuster, J. Chem. Educ. 2003, 80, 679 – 690.

[2] J. G. Hoggett, R. B. Moodie, J. R. Penton, K. Schofield, Nitrationand Aromatic Reactivity, Cambridge University Press, GreatBritain, 1971, p. 47.

[3] G. A. Olah, R. Malhotra, S. C. Narang, Nitration Methods andMechanism, VCH, New York, 1989.

[4] G. W. Wheland, J. Am. Chem. Soc. 1942, 64, 900 – 908.[5] a) T. Ahrens, J. Kohlmann, M. Ahrens, T. Braun, Chem. Rev.

2015, 115, 931 – 972; b) O. Allemann, S. Duttwyler, P. Romanato,K. K. Baldridge, J. S. Siegel, Science 2011, 332, 574 – 577.

[6] a) M. D. Struble, M. T. Scerba, M. A. Siegler, T. Lectka, Science2013, 340, 57 – 60; b) M. D. Struble, M. G. Holl, M. T. Scerba,M. A. Siegler, T. Lectka, J. Am. Chem. Soc. 2015, 137, 11476 –11490.

[7] A. M. Tafesh, J. Weiguny, Chem. Rev. 1996, 96, 2035 – 2052.[8] E. D. Hughes, C. K. Ingold, R. I. Reed, J. Chem. Soc. 1950,

2400 – 2440.[9] P. M. Esteves, J. W. de M. Carneiro, S. P. Cardoso, A. G. H.

Barbosa, K. K. Laali, G. Rasul, G. K. S. Prakash, G. A. Olah, J.Am. Chem. Soc. 2003, 125, 4836 – 4849.

[10] We assume that the electronic effects of fluorine on the Whelandintermediate will parallel its effect on analogous p-complexes:J. F. de Queiroz, J. W. de M. Carneiro, A. A. Sabino, R.Sparrapan, M. N. Eberlin, P. M. Esteves, J. Org. Chem. 2006,71, 6192 – 6203.

[11] M. T. Scerba, S. Bloom, N. Haselton, M. Siegler, J. Jaffe, T.Lectka, J. Org. Chem. 2012, 77, 1605 – 1609.

[12] D. Biermann, W. Schmidt, J. Am. Chem. Soc. 1980, 102, 3163 –3173.

[13] E. Pretsch, P. Bîhlmann, M. Badertscher, Structure Determina-tion of Organic Compounds, Springer, Zurich, 2008, p. 250.

[14] W. R. Dolbier, Jr., Guide to Fluorine NMR for Organic Chem-ists, Wiley, Hoboken, 2009, p. 75.

[15] I. Alkorta, J. Elguero, New J. Chem. 1998, 22, 381 – 385.[16] S. Dell, N. J. Vogelaar, D. M. Ho, R. A. Pascal, Jr., J. Am. Chem.

Soc. 1998, 120, 6421 – 6422.[17] Y. Chang, L. Ho, T. Ho, W. Chung, J. Org. Chem. 2013, 78,

12790 – 12794.[18] a) Gaussian09, RevisionA.1, M. J. Frisch, et al. Gaussian, Inc.,

Wallingford CT, 2009 ; b) D. Chai, M. Head-Gordon, Phys.Chem. Chem. Phys. 2008, 10, 6615 – 6620.

[19] A. C. de Dios, E. Oldfield, Chem. Phys. Lett. 1993, 205, 108 – 116.[20] C. Foroutan-Nejad, S. Shahbazian, P. Rashidi-Ranjbar, Phys.

Chem. Chem. Phys. 2010, 12, 12630 – 12637.[21] a) M. D. Struble, J. Strull, K. Patel, M. A. Siegler, T. Lectka, J.

Org. Chem. 2014, 79, 1 – 6; b) R. A. Pascal, Jr., Eur. J. Org.Chem. 2004, 3763 – 3771.

[22] N. H. Martin, N. W. Allen III, E. K. Minga, S. T. Ingrassia, J. D.Brown, J. Am. Chem. Soc. 1998, 120, 11510 – 11511.

[23] E. Kleinpeter, S. Klod, J. Am. Chem. Soc. 2004, 126, 2231 – 2236.[24] I. Nowak, J. Fluorine Chem. 1999, 99, 59 – 66.[25] T. Takemura, T. Sato, Can. J. Chem. 1976, 54, 3412 – 3418.[26] E. R. Johnson, S. Keinan, P. Mori-Sanchez, J. Contreras-Garcia,

A. J. Cohen, W. Yang, J. Am. Chem. Soc. 2010, 132, 6498 – 6506.[27] a) T. Yanai, D. Tew, N. Handy, Chem. Phys. Lett. 2004, 393, 51 –

57; b) A. Austin, G. Petersson, M. J. Frisch, F. J. Dobek, G.Scalmani, K. Throssell, J. Chem. Theory Comput. 2012, 8, 4989;c) O. A. Vydrov, G. E. Scuseria, J. Chem. Phys. 2006, 125,234109.

[28] a) Z. Pechlivanidis, H. Hopf, J. Grunenberg, L. Ernst, Eur. J.Org. Chem. 2009, 238 – 252; b) H. J. Reich, D. J. Cram, J. Am.Chem. Soc. 1969, 91, 3534 – 3543.

[29] AIMAll (Version 13.05.06), T. A. Keith, TK Gristmill Software,Overland Park KS, USA, 2013 (http://aim.tkgristmill.com).

[30] J. V. Crivello, J. Org. Chem. 1981, 46, 3056 – 3060.[31] G. A. Smythe, G. Matanovic, D. Yi, M. W. Duncan, Nitric Oxide

1999, 3, 67 – 74.[32] S. C. Suri, R. D. Chapman, Synthesis 1988, 743 – 745.[33] O. Diels, K. Alder, Liebigs Ann. Chem. 1931, 490, 236 – 242.[34] J. E. McMurry, T. Lectka, Acc. Chem. Res. 1992, 25, 47 – 53.

Received: February 29, 2016Revised: March 14, 2016Published online: April 26, 2016

Figure 5. Relative rate study of nitrations of 1 and controls. Condi-tions: ammonium nitrate in a 2:3 mixture of TFAA and MeCN, roomtemperature.

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